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Adult resident stem cells are capable of regenerating tissues that manifest signs of "rejuvenation" in flatworms and mice of older ages. These findings suggest potentially conserved regulatory mechanisms of adult resident stem cells from worms to mammals. Regenerative capacities are more limited in specific tissues and stem cell types of larger mammals. Understanding and harnessing the rejuvenating properties of resident adult stem cells in flatworms and mice could have broad therapeutic implications for improving stem cell function and tissue plasticity across organ systems of humans in advanced age.